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Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation

Abstract

A goal of molecular genetics is to understand the relationship between basic nuclear processes, epigenetic changes and the numerous proteins that orchestrate these effects. One such protein, ATRX, contains a highly conserved plant homeodomain (PHD)-like domain, present in many chromatin-associated proteins, and a carboxy-terminal domain which identifies it as a member of the SNF2 family of helicase/ATPases1,2. Mutations in ATRX give rise to characteristic developmental abnormalities including severe mental retardation, facial dysmorphism, urogenital abnormalities and α-thalassaemia1. This circumstantial evidence suggests that ATRX may act as a transcriptional regulator through an effect on chromatin. We have recently shown that ATRX is localized to pericentromeric heterochromatin during interphase and mitosis, suggesting that ATRX might exert other chromatin-mediated effects in the nucleus. Moreover, at metaphase, some ATRX is localized at or close to the ribosomal DNA (rDNA) arrays on the short arms of human acrocentric chromosomes3. Here we show that mutations in ATRX give rise to changes in the pattern of methylation of several highly repeated sequences including the rDNA arrays, a Y-specific satellite and subtelomeric repeats. Our findings provide a potential link between the processes of chromatin remodelling, DNA methylation and gene expression in mammalian development.

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Figure 1: Localization of ATRX on metaphase chromosomes.
Figure 2: Changes in the pattern of methylation at rDNA in ATR-X syndrome.
Figure 3: The pattern of methylation throughout the rDNA array.
Figure 4: Methylation changes in ATR-X patients.
Figure 5: The pattern of methylation throughout the Y-specific satellite repeats (DYZ2) and repeats of the TelBam3.4 family.

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Acknowledgements

We thank W.R.A. Brown and D. Jackson for probes; M. Valdivia for anti-UBF antibodies; V.J. Buckle for helpful advice; D. Jackson for probes to detect the human ribosomal DNA arrays; T. Jones and I. Smith for help with the analysis of methylcytosine levels using HPLC; and D.J. Weatherall for support and encouragement. The work was supported by the MRC, the Wellcome Trust (R.J.G.), Action Research (D.M.O.) and the C.J. Marin Travelling Fellowship (D.G.).

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Correspondence to Douglas R. Higgs.

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Gibbons, R., McDowell, T., Raman, S. et al. Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation. Nat Genet 24, 368–371 (2000). https://doi.org/10.1038/74191

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